Although transplantation of organs is becoming commonplace, rejection of the donated organ by the patient remains a serious problem. Except for cases of organ donation between identical twins or the special instance of transplantation in individuals with severe combined immunodeficiency disease, all transplant recipients currently require an immunosuppressive regimen to prevent rejection. Although these immunosuppressive drugs are administered post-transplantation in an attempt to prevent rejection, they also suppress the body's defenses against infection. Thus, transplantation requires a continued effort to induce acceptance of the graft without paralyzing the body's immune system.
Various regimens in use employ one or more of the following agents or therapies: (1) corticosteroids, such as prednisone; (2) cytotoxic drugs, such as azathioprine and cyclophosphamide; (3) x-ray irradiation therapy; (4) anti-lymphocyte and anti-thymocyte globulins; (5) cyclosporine; and (6) monoclonal antibodies such as OKT3, which reacts specifically with the CD3 antigen-recognition structure of human T cells and blocks the T cell effector function involved in allograft rejection.
All of the above described therapy methods are administered post-transplant and have undesirable side effects. For example, corticosteroids may cause decreased resistance to infection, painful arthritis, osteoporosis, and cataracts. Cytotoxic agents may cause anemia and thrombocytopenia, and sometimes hepatitis. The antilymphocyte globulins may cause fever, hypotension, diarrhea, or sterile meningitis. Cyclosporine may cause decreased renal function, hypertension, tremor, anorexia, and elevated low-density lipoprotein levels. OKT3 may cause chills and fever, nausea, vomiting, diarrhea, rash, headache, photophobia, and occasional episodes of life-threatening acute pulmonary edema.
There are two types of allograft rejection, acute humoral rejection (hyperacute rejection) and acute cellular rejection (acute rejection). Hyperacute humoral rejection is generally an overwhelming, irreversible process that occurs when organs are transplanted into recipients who have preformed cytotoxic antibodies against antigens of the donor allograft, such as anti-HLA antibodies (i.e., immunohistoincompatibility). Up until now, no combination of immunosuppressive drugs has been capable of reversing or inhibiting this rapid hyperacute rejection process.
Intravenous gammaglobulin (IVIg) has been in use since 1981, primarily for prophylaxis in those with primary or secondary immunodeficiency states. Beneficial results have also been reported in the treatment of childhood idiopathic thrombocytopenic purpura, in CMV prophylaxis for bone marrow transplantation, amelioration of GVHD (graft versus host disease), and other autoimmune disorders. IVIg is known to contain antiidiotypic antibody activity against a number of autoantibodies (i.e., anti-ANA and anti-ANCA), but little is known about IVIg's antiidiotypic activity against alloantibodies. IVIg is known to block antibody response in vivo and in vitro although the exact mechanisms are not known. IVIg has been used successfully to obtain improved post transfusion platelet increments in refractory patients.
A wide source of donor organs are potentially available to various patients in need of a transplant. However, due to positive crossmatch that is typically observed between a highly sensitized organ-recipient and organ-donor, only a very small percentage of available donor-organs are actually suitable for transplant for any given potential organ-recipient. Thus, methods useful for increasing the percentage of donor-organs available to organ-recipient candidates are needed.